Periodontal disease is a common and widespread disease which has been shown to be a result of pathogenic bacterial infection established within the gingival sulcus. This condition, if not arrested, will cause formation of a periodontal pocket. The bacteria found in the periodontal pocket are more anaerobic and contain more gram-negative organisms than bacteria found supragingivally.
Conventional therapy and treatment of periodontal disease in humans involves the mechanical removal of bacterial plaque and other accumulated debris from the periodontal pocket, often called root planing and scaling. More severe cases may require periodontal surgery to remove damaged tissue. These procedures are expensive, painful, cause extensive bleeding and, accordingly, are not well accepted by patients. These procedures are also temporary at best, and frequent recall visits to the dental surgeon are often necessary.
Several factors reduce the effectiveness of supragingival application of drugs or other medicaments in treating periodontal disease. For example, the close proximity of the gum tissue to a tooth impairs diffusion of a medicament into a periodontal pocket. Also, a crevicular fluid is continually produced in the pocket and flows outwardly. The crevicular fluid flows out of the pocket at a rate of about 1 to 5 microliters per hour in healthy periodontal tissue and at a rate of about 10 to 100 microliters per hour in diseased periodontal tissue.
As a result, the penetration of topically or supragingivally applied medicaments has been largely ineffective in the treatment of periodontal disease. With topical application, the medicaments penetrate no more than about 2 mm into a periodontal pocket and are quickly washed out by the crevicular fluid outflow. Since periodontal pockets can be about 5 mm or greater in depth, topical application does not provide an effective means for treating diseased periodontal pockets.
Many techniques have been proposed for treatment of periodontal disease, e.g. drug-containing lozenges which slowly dissolve in the mouth, drug-containing chewing gums, topical buccal bandages and dressings, topically applied compositions (e.g., waxes, pastes, creams and ointments) and drug-impregnated dental floss. These techniques, however, are not effective in delivering a drug into a diseased periodontal pocket for the reasons outlined above.
Systemic application of drugs such as tetracycline for the treatment of periodontal disease is also known. Unfortunately, the systemic application of an antibiotic results in very low concentrations of antibiotic delivered to the diseased site (e.g., the periodontal pocket). There is also a greater opportunity for an adverse systemic reaction to a drug administered systemically compared to localized administration.
In order to overcome the disadvantages of topical treatments and systemic administration of antibiotics in order to treat periodontal disease, drug delivery devices suitable for placement directly in the periodontal pocket have been developed. For example, U.S. Pat. No. 4,568,535 discloses a delivery device comprising an ethylcellulose film containing metronidazole which is placed in a periodontal pocket for a period of days during which the metronidazole is slowly released. After the metronidazole is released, the film must then be surgically removed from the pocket. Antibiotic (e.g., tetracycline) containing fibers have also been inserted into the periodontal pocket to treat periodontal disease. See, for example, U.S. Pat. No. 4,175,326. After the antibiotic has been completely delivered, the fibers must be removed, requiring a follow-up visit to the dentist. In addition, the placement of fibers in the periodontal pocket has been found by certain individual practitioners to be somewhat time-consuming, thereby raising the cost of the treatment.
In response to these problems, bioerodible drug delivery devices have been proposed for treating periodontal disease. The delivery device typically includes an antibiotic dispersed in a bioerodible and biocompatible material. The device has a size and shape suitable for insertion into the periodontal pocket (e.g., in the shape of a fiber; see U.S. Pat. No. 4,764,377). The bioerodible material may be polymeric and it may be natural (e.g., collagen) or synthetic (e.g., a polylactide). After insertion into the periodontal pocket, the antibiotic is released slowly over a period of days. Following delivery of the drug, the material erodes and the erosion products are washed out of the pocket by the normal outflow of gingival fluid. Typically, the erosion products are swallowed and eventually excreted by the body. Since the material erodes in-situ within the periodontal pocket, there is no need for a follow-up visit to the dental surgeon in order to remove the drug delivery device.
While the use of bioerodible delivery devices represents a major step forward in the treatment of periodontal disease, there remains a need in the art for a device which can be more quickly and easily placed in a tissue pocket, such as a periodontal pocket, and will conform more exactly to the size and shape of each individual pocket for the release of a beneficial agent in order to treat a disease condition.
Baker in U.S. Pat. No. 4,780,320 describes a system for delivering drug to a periodontal pocket which comprises drug-containing biodegradable microparticles or microcapsules in a fluid carrier medium which are injected into the pocket with a syringe. These small particles, however, have several disadvantages when used in a tissue pocket. When they are inserted into body cavities such as a periodontal pocket, the eye or the vagina where there is considerable fluid flow, these small particles are poorly retained because of their small size and discontinuous nature, particularly when present in a fluid medium, and can easily be squeezed or flow out of the tissue pocket opening. A further limitation to the use of microparticles is their lack of reversibility without extensive intervention. That is, if there are complications after they have been injected, it is considerably more difficult to remove them from the body than with more solid implants.
Bucalo in U.S. Pat. Nos. 3,982,537, 4,030,499 and 4,054,138 describes a material formed of hydrogenated vegetable oil or animal fat for implanting into internal tissue. The hydrogenated oil/fat melts upon heating to a temperature of about 130 .degree. F. (55.degree. C.). The material is mixed with the drug or antibiotic and injected into the internal tissue in a molten state. Once the material is injected, it cools to body temperature and hardens to a soft pliable solid material. The material eventually dissolves over time and is absorbed into the surrounding tissues. Unfortunately, this material has several disadvantages. The hydrogenated vegetable oil or animal fat is not well suited for retention in a periodontal pocket, which is not an internal tissue but has a large opening that communicates with the exterior environment. There is a natural tendency for gum tissues surrounding the roots of teeth to exert pressure thereon. As a result, soft pliable fats and oils can be quickly squeezed out through the opening of the periodontal pocket. This condition is exacerbated by normal patient activity such as chewing and swallowing, resulting in the material being squeezed out of the pocket before the drug delivery regimen can be completed. Additionally, the materials of Bucalo must be absorbed into the surrounding body tissue, which greatly limits the choice of materials that can be used.
Wahlig et al. in U.S. Pat. No. 4,853,225 describe polysaccharide implants which can be liquids at temperatures above body temperature and gels at body temperature. However, polysaccharides are a natural food source for bacteria, thus providing a substrate for bacterial growth. As a result, compositions comprising polysaccharides are not good choices for use in a body tissue pocket open to the environment, particularly to pockets in the mouth where large numbers of bacteria are continuously being introduced. Additionally, the viscosities of gellated polysaccharides are relatively low, and polysaccharide implants would tend to flow or be squeezed out through the opening of a body tissue pocket.
Dunn et al. in U.S. Pat. No. 4,938,763 describes biodegradable polymeric implants that are formed in-situ in the body. The polymer is placed into the animal in liquid form and cures to form the implant in-situ. This is done either by 1) a thermoplastic system formed by dissolving a non-reactive polymer in biocompatible solvent to form a liquid, placing the liquid within the animal, and allowing the solvent to dissipate to produce the implant; or by 2) a thermosetting system formed by mixing together a liquid acrylic ester-terminated, biodegradable prepolymer and a curing agent, placing the liquid mixture within an animal, and allowing the prepolymer to cure to form the implant. However, these systems are inconvenient to use in that they must be mixed at the time of implantation, resulting in additional steps and extra time for the doctor or technician, and then must be placed immediately into the pocket before the polymer cures and solidifies.
Thus, there has been a need in the art for a drug delivery platform which can be quickly and easily placed in a tissue pocket, such as a periodontal pocket; which is not easily expelled from the pocket by physiological conditions such as fluid flow or normal patient activities, such as chewing and swallowing; and which erodes in-situ within the pocket.